Urinary CTX-II concentrations are elevated and associated with knee pain and function in subjects with ACL reconstruction

Chmielewski, Terese L.; Trumble, Troy N.; Joseph, Anna Maria; Shuster, Jonathan J.; Indelicato, Peter A.; Moser, Michael W.; Cicuttini, Flavia Maria; Leeuwenburgh, Christiaan

doi:10.1016/j.joca.2012.07.014

Cited by 34 publications

(62 citation statements)

References 40 publications

(55 reference statements)

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“…While this induction is thought to be due to ROS production from XO, it is possible that it is operating through other means, which would explain the lack of association found between CPII and ROS+RNS or carbonyl. While other studies have shown an increase in cartilage degradation with joint trauma as measured by CTx-II [31,34,35], we found no such increase. It is probable that the acute timepoint of most of our injury samples (mean 12 days) is the most likely explanation as collagen degradation products begin to be significantly elevated in the SF about 47 days after injury [36].…”

Section: Discussioncontrasting

confidence: 99%

Xanthine oxidase injurious response in acute joint injury

Stäbler

Zura

Hsueh

et al. 2015

Clinica Chimica Acta

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Background While acute trauma is a major cause of osteoarthritis, its etiology is poorly understood. We sought to determine whether xanthine oxidase (XO), a major producer of reactive oxygen species, plays a role in the early events of acute joint injury. Methods We analyzed synovial fluid from 23 subjects with recent severe acute knee injury. As a control we evaluated SF from 23 individuals with no or minimal knee osteoarthritis. We measured XO activity, reactive oxygen+reactive nitrogen species (ROS+RNS), protein oxidative damage (carbonyl), the type II collagen synthesis marker procollagen II c-propeptide (CPII) and the type II collagen degradation marker collagen type II telopeptide (CTx-II). We also measured the proinflammatory cytokine IL-6. Results XO and ROS+RNS were higher (p=0.02 and p=0.001 respectively) in acute injury than control and were strongly positively associated (r=0.62, p=0.004). Carbonyl was higher in acute injury than control (p=0.0002) and was positively correlated with XO (r=0.68, p=0.0007) as well as with ROS+RNS (r=0.71, p=0.004). CPII was higher in acute injury than control (p<0.0001) and was negatively correlated with XO (r=−0.49, p=0.017). While CTxII was not significantly higher in acute injury than control, it was positively correlated with CPII (r=0.71, p=0.0002). IL-6 was higher in acute injury than control (p<0.0001). Conclusions These results are consistent with a potentially injurious effect of XO activity in acute joint injury characterized by excess free radical production and oxidative damage. These effects are associated with an inhibition of type II collagen production that may impede the ability of the injured joint to repair.

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Section: Discussioncontrasting

confidence: 99%

Xanthine oxidase injurious response in acute joint injury

Stäbler

Zura

Hsueh

et al. 2015

Clinica Chimica Acta

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“…Our observations of the present prospective large cohort of patients with ACL rupture (i.e., an increased release of aggrecan ARGS neoepitope resulting from increased aggrecanase activity) extend the findings of 1 longitudinal and several cross-sectional studies of kneeinjured patients in whom levels of aggrecan fragments (6,15) and aggrecan ARGS neoepitope fragments (12)(13)(14) were found to be increased early after injury but to be close to normal later after injury. Our finding of increased urine CTX-II concentrations in the acute phase of ACL injury extend and support findings of prior cross-sectional studies showing an increase of CTX-II in synovial fluid, serum, and urine following knee injury (4,21). The strong positive correlation between urine CTX-II and NTX-I in young adults after 1822 STRUGLICS ET AL knee injury is notable and consistent with suggestions that CTX-II, representing a type II collagen degradation product, may be more closely related to turnover of calcified cartilage and bone than to turnover of hyaline joint cartilage (35).…”

Section: Discussionsupporting

confidence: 90%

Changes in Cytokines and Aggrecan ARGS Neoepitope in Synovial Fluid and Serum and in C‐Terminal Crosslinking Telopeptide of Type II Collagen and N‐Terminal Crosslinking Telopeptide of Type I Collagen in Urine Over Five Years After Anterior Cruciate Ligament Rupture: An Exploratory Analysis in the Knee Anterior Cruciate Ligament, Nonsurgical Versus Surgical Treatment Trial

Struglics

Larsson

Kumahashi

et al. 2015

Arthritis & Rheumatology

161

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Objective. To prospectively monitor levels of proinflammatory cytokines and aggrecan ARGS neoepitope in synovial fluid and serum as well as levels of C-terminal crosslinking telopeptide of type II collagen (CTX-II) and N-terminal crosslinking telopeptide of type I collagen (NTX-I) in urine after acute anterior cruciate ligament (ACL) rupture.Methods. Synovial fluid, serum, and urine were collected from 121 adults on 6 occasions over 5 years after acute ACL injury. Reference samples were obtained from subjects without knee injury. Concentrations of interleukin-6 (IL-6), IL-8, IL-10, interferon-g (IFNg), tumor necrosis factor (TNF), aggrecan ARGS neoepitope, CTX-II, and NTX-I were measured by enzymelinked immunosorbent assay.Results. Shortly after ACL injury, cytokine concentrations in synovial fluid were elevated 6-fold (TNF) to 1,050-fold (IL-6) compared to reference levels, while concentrations of aggrecan ARGS neoepitope in synovial fluid and serum and CTX-II in urine were elevated 1.4-fold to 8-fold. Thereafter, concentrations of cytokines and aggrecan ARGS neoepitope in synovial fluid decreased with different half-lives (in years: IL-6 0.9, IL-8 2.2, IL-10 2.3, IFNg 3.1, TNF 3.6, aggrecan ARGS neoepitope 4.0). After 5 years, the TNF concentration in synovial fluid remained higher than the reference level. There was a correlation between the concentrations of aggrecan ARGS neoepitope in synovial fluid and serum (r s 5 0.36). Concentrations of aggrecan ARGS neoepitope in synovial fluid and of CTX-II and NTX-I in urine were correlated with concentrations of cytokines in synovial fluid (r s 5 0.41-0.49 and r s 5 0.21-0.31, respectively).Conclusion. Acute ACL injury induced highly increased levels of inflammatory cytokines in the joint, and these were associated with proteolysis of aggrecan and type II collagen. Cytokine levels remained increased up to 5 years after injury, indicative of extended local inflammation in the joint.

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“…CTX-II is highly correlated with the occurrence, development, injury degree, bone marrow lesion and osteophyte formation of OA [12,13]. For patients with (ACLR) undergoing anterior cruciate ligament reconstruction, their level of CTX-II decreased with the relief of pain and improvement of physical function, and the decrease of CTX-II content indicated a decrease in the severity of the disease [14]. Based on this, in order to verify the hypothesis that CTX-II and C2C can be used as biomarkers of OA joint of knee joint.…”

Section: Introductionmentioning

confidence: 99%

Potential value of combining CTX-II with C2C in evaluating and diagnosing early rat osteoarthritis

Shen¹,

Zhang²,

Ma³

et al. 2020

Preprint

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Background This article aims to study the changes of CTX-II and C2C biomarker concentrations during the pathogenesis of osteoarthritis with SD rats as the research object. Through the longitudinal and joint detection of the content of CTX-II and C2C markers in the serum of anterior cruciate ligament resection (ACLT) rats, the evaluation and early diagnosis of OA disease can be realized, and the theoretical basis for the rapid diagnosis technology of OA can be provided. Methods SD rats were randomly divided into two groups: Sham operation group and OA model group. The OA model was established by anterior cruciate ligament excision (ACLT) for 2, 4, 6, 8, and 10 weeks, respectively. The cartilage gross score and Mankin score were used to evaluate the model. The tibia of the right hind limb was sampled for pathological histology and HE staining. The collected blood samples are used to detect changes in the concentration of CTX-II and C2C in serum. The receiver operating characteristic curve (ROC) was used to compare the area under the curve (AUC) of CTX-II, C2C and combined biomarkers. Results In the model group, the content of CTX-II and C2C in SD rat serum increased significantly, and the content of CTX-II and C2C increased with the prolonged modeling time, which was time dependent; The levels of CTX-II and C2C in the serum of rats in the sham operation group did not change significantly; both macroscopic observations and Mankin scores increased significantly. The AUC of the combined biomarker is higher than that of CTX-II and C2C. Finally, CTX-II and C2C levels were positively correlated with Mankin score. Conclusion Early combined detection of serum CTX-II and C2C concentrations has potential value for the evaluation and diagnosis of osteoarthritis.

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Urinary CTX-II concentrations are elevated and associated with knee pain and function in subjects with ACL reconstruction

Cited by 34 publications

References 40 publications

Xanthine oxidase injurious response in acute joint injury

Xanthine oxidase injurious response in acute joint injury

Potential value of combining CTX-II with C2C in evaluating and diagnosing early rat osteoarthritis

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